We propose to study further the regulation of cholesterol synthesis in human fibroblasts, and to characterize the critical enzyme in this pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase). We propose to study the characteristics of the low density lipoprotein receptor that regulates cholesterol synthesis in human fibroblasts. We will also explore the nature of the defect in this receptor that appears to be the primary genetic lesion in Familial Hypercholesterolemia. BIBLIOGRAPHIC REFERENCES: Goldstein, J.L. and Brown, M.S. (1975) Lipoprotein receptors, cholesterol metabolism and atherosclerosis. Arch. Pathol. 99: 181-184. Brown, M.S., Dana, S.E., and Goldstein, J.L.: Cholesterol ester formation in cultured human fibroblasts: Stimulation by oxygenated sterols. J. Biol. Chem. In press, l975.